A protein specifically expressed on a tumor cell surface is useful as a cell surface marker for cancer diagnosis using peripheral blood, bone marrow cells, tissues, and the like of a patient, and is also applicable to evaluation of an effect of cancer treatment and monitoring of recurrence by examining the presence or absence of expression of the protein.
In addition, in recent years, an antibody drug which targets a protein specifically expressed on a tumor cell surface has been actively developed. A therapeutic method using an antibody drug has attracted attention as a therapeutic method which has a minimal influence on normal cells and can be expected to provide a therapeutic effect having high selectivity for tumor cells by selecting as a target an antigen which is not expressed or is expressed in a very small amount in normal cells. An antibody as an active ingredient of the antibody drug has a variety of modes (mechanisms) of action. For example, a therapeutic drug for B cell lymphoma, rituximab, which uses a monoclonal antibody produced against a CD20 antigen specifically expressed in B cells, has actions such as induction of apoptosis, an antibody-dependent cellular cytotoxicity (ADCC) activity, and a complement-dependent cytotoxicity (CDC) activity on tumor cells. Further, yttrium (90Y) ibritumomab tiuxetan, in which a radioisotope is bound to an anti-CD20 monoclonal antibody, is expected to provide a therapeutic effect by radiation as well as attack on tumor cells by the antibody, and has been found to be useful for treatment of recurrent or refractory B-cell lymphoma.
Under current circumstances, however, applications of a monoclonal antibody useful for tumor treatment are limited to several kinds of tumors such as metastatic breast cancer, acute myeloid leukemia, refractory chronic lymphoma, non-Hodgkin's lymphoma, and multiple myeloma.
Accordingly, a novel cell surface marker specific for tumor cells, which is applicable to cancer diagnosis and cancer treatment using an antibody drug, has been actively searched.
LDL receptor relative with 11 ligand-binding repeats (LR11) was a novel LDL receptor-like protein identified as having a characteristic structure to the LDL receptor family (Patent Document 1 and Non Patent Document 1). Expression of LR11 is reported to be promoted specifically invascular intima thickened sites formed by migration and proliferation of smooth muscle cells (Non Patent Document 2). The inventors found that: soluble LR11 was present in blood of mammals and concentrations of soluble LR11 in blood of arteriosclerosis disease patients showed significantly higher values than those of healthy subjects (Patent Document 2). In addition, the inventors developed a method to measure soluble LR11 in blood or bone marrow aspirates simply and exactly (Patent Document 3 and Non Patent Document 4), and measured concentrations of soluble LR11 in various diseases. As a result, the inventors confirmed that the concentrations of soluble LR11 showed abnormally high values in malignant tumors, in particular, hematopoietic tumor diseases such as leukemia and malignant lymphoma, and found that soluble LR11 in blood served as a novel tumor marker (Patent Document 4). However, the concentrations of soluble LR11 do not always show abnormally high values in blood of all hematopoietic tumor disease patients, and a reason for that has not been clarified yet.
Meanwhile, Non Patent Document 5 reports that LR11 mRNA is expressed in a wide range of human-derived tissues (nerve tissues, liver, brain, and peripheral leukocytes). In addition, the document describes that the expression of LR11 mRNA is promoted in a CD34+CD38-fraction (myeloid leukemia cells) in which stem cells in human bone marrow cells are present, and although data is not shown, LR11 mRNA is expressed in part of hematopoietic tumor culture cells as well. However, Non Patent Document 5 merely describes exhaustive gene expression analysis in blood precursor cells including culture cells, does not describe any tissue expressing LR11 at a protein level, and also does not describe any relationship between a hematopoietic tumor and expression of LR11 mRNA at all.